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Plasminogen activation system indices in basal cell carcinoma.

e21559 Background: The plasminogen activation system plays a key role in maintaining tissue homeostasis, participating in fibrinolysis and the remodeling of the extracellular matrix and basement membranes. Its main components include plasminogen, its activators (tissue plasminogen activator [tPA] and urokinase plasminogen activator [uPA]), and their inhibitors (PAI-1, PAI-2). Under physiological conditions, the system regulates wound healing, embryogenesis, and inflammation. However, its dysregulation in pathological states, such as cancer, contributes to tumor progression, including invasion, angiogenesis, and metastasis. This study aimed to investigate the levels and activity of fibrinolytic system components (uPA, tPA, PAI-1, α₂-antiplasmin [α₂-AP], α₂-macroglobulin [α₂-MG]) in tumor tissue and the perifocal zone in superficial and solid forms of basal cell carcinoma (BCC) in men and women. Methods: The study used samples of tumor and perifocal zone tissue from 60 patients with stage I–II BCC. The control group consisted of 20 samples of intact skin obtained during plastic surgeries. Concentrations of plasmin-α₂-antiplasmin complex (PAP) and levels/activity of tPA, uPA, PAI-1, α₂-AP, and α₂-MG were determined by enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed using Statistica 10.0 software. Results: Tumor tissue from all patients showed a 1.5–3.9-fold increase in uPA and tPA levels and activity and a 1.5–8.9-fold increase in PAI-1 content, alongside a 1.6–2.9-fold decrease in PAP. Patients with the superficial BCC type exhibited a more than 3-fold increase in α₂-AP in tumor samples. In most cases, perifocal zone indices did not differ from control values. An exception was three male patients with the solid BCC type, in whom elevated levels and activity of uPA and tPA, increased PAI-1 content, and high PAP levels were detected in both tumor and perifocal zones. During follow-up, these patients developed local recurrences within 12–15 months. Conclusions: The data indicate an imbalance in the plasminogen activation system in BCC tissue. Elevated levels of uPA, tPA, PAI-1, and PAP in the perifocal zone suggest an expansion of the tumor’s metabolic field and the formation of a microenvironment conducive to recurrence, identifying them as potential biomarkers for predicting local relapse in basal cell carcinoma.

First-in-human results with IMA401, a MAGEA4/8-targeted T-cell receptor–based bispecific T-cell engager (TCER) in recurrent or refractory solid tumors.

2507 Background: IMA401 is a next-gen bispecific TCR-based T-cell engager designed to redirect T cells to antigen-positive cancer cells. It combines a high-affinity, highly specific TCR domain against an HLA-A*02:01-presented target peptide common to cancer-specific antigens MAGEA4 and MAGEA8 with a low-affinity T-cell–recruiting domain for improved tolerability and biodistribution, and an Fc part for half-life extension. IMA401-101 (NCT05359445) is a first-in-human phase 1a/b basket study evaluating IMA401 in pts with advanced solid tumors. Methods: Pts were ≥18 y, HLA-A*02:01+, MAGEA4+ and/or MAGEA8+, have R/R solid tumors, measurable disease (RECIST 1.1), ECOG performance status 0-2, and have exhausted SOC options. Dose escalation involved cohorts of 1-6 pts using adaptive design (BLRM). Doses ranged from 0.0066 mg - 2.5 mg IMA401 q2w (± pembrolizumab [pembro] q6w with 1.0 mg or 1.5 mg IMA401). Weekly step dosing of IMA401 was implemented for the first 2-3 doses at ≥1 mg . Primary endpoint was MTD assessed by BLRM and/or RP2D as monotherapy and in combination with pembro. Secondary endpoints included safety and initial antitumor activity (confirmed objective response rate [cORR] and disease control rate [DCR]). Results: As of Sep 26, 2025, 55 heavily pretreated pts across > 15 different tumor types with a median of 4 prior lines of therapy (range 1-9) received IMA401 ± pembro. Most frequent TRAEs were low-grade CRS (G1: 24%; G2: 11%; no ≥G3 events), expected and transient lymphopenia (any grade: 29%; ≥G3: 24% which typically improved within 1-3 days), and reversible neutropenia (any grade: 29%; ≥G3: 18%). No ICANS was observed. Tolerability of IMA401 + pembro (n = 9) was consistent with the IMA401 monotherapy safety profile. MTD was not reached (3 DLTs at 2.5 mg IMA401). RP2D range was determined to be 1-2 mg IMA401. Efficacy was evaluable in 38 pts receiving a target dose of ≥1 mg IMA401. Promising clinical activity was noted in pts with head and neck (HN) cancer (cORR: 25% [2/8]; DCR: 63% [5/8]) and melanoma (cORR: 29% [2/7]; DCR: 57% [4/7]) with duration of all confirmed responses beyond 6 months postinfusion. In squamous non-small cell lung cancer (sqNSCLC [n = 3]), 1 PR with reduction in all target lesions, 1 SD with OS of ~16 months and 1 PD with reduction in all liver target lesions were observed. After data cutoff, 2 more cPRs were observed in HN cancer resulting in a cORR of 33% (4/12). An updated full dataset will be presented. Conclusions: IMA401 demonstrated overall favorable tolerability without reaching formal MTD and encouraging antitumor activity in pts with HN cancer, melanoma, and sqNSCLC at RP2D range. Based on the promising results and preclinical proof of concept data, further development steps are being evaluated including a potentially synergistic combination with the PRAME-directed bispecific IMA402 in sqNSCLC and other solid tumor indications. Clinical trial information: NCT05359445 .

Cohort-level safety and efficacy results for [ ²¹² Pb]VMT-α-NET in advanced somatostatin receptor subtype 2 (SSTR2+)–expressing neuroendocrine tumors (NETs): Cohorts 1–3.

4173 Background: [ 212 Pb]VMT-α-NET is an alpha-particle radiation-delivering agent targeted to somatostatin receptor type 2 (SSTR2)-expressing tumors. Here, we present safety and efficacy results from the dose-finding phase 1/2a clinical trial (NCT05636618). Methods: This phase 1/2a dose-escalation study uses a Bayesian algorithm to identify an optimal dose of [ 212 Pb]VMT-α-NET for participants with advanced, well-differentiated NETs expressing SSTR2. Eligible participants must have unresectable or metastatic disease, documented radiologic progression following at least one prior systemic treatment, and evidence of SSTR2 expression (Krenning Score ³2) in ≥1 lesion confirmed on an FDA-approved somatostatin receptor PET scan. Patients previously treated with systemic peptide receptor radionuclide therapy (PRRT) are excluded from enrollment. During the dose-finding phase, participants may receive up to four administrations of [ 212 Pb]VMT-α-NET at their assigned dose level, and they are monitored for dose-limiting toxicities (DLTs) for 42 days and safety throughout the study. Efficacy is evaluated by investigators according to RECIST criteria v1.1. Dosimetry is included as a supportive analysis. Results: As of the 10-Dec-2025 data cut-off (DCO), 56 participants had been enrolled across Cohorts 1, 2, and 3 and received at least one dose of [ 212 Pb]VMT-α-NET: 2 participants in Cohort 1 (2.5 mCi), 46 in Cohort 2 (5 mCi), and 8 in Cohort 3 (6 mCi). No dose-limiting toxicities, grade 5 adverse events, treatment-related discontinuations, serious renal events, dysphagia, or clinically meaningful treatment-related myelosuppression were observed. The median follow-up for all treated participants was 40 weeks (range 6–97). Efficacy has been summarized in this abstract for 25 participants (2 in Cohort 1 and 23 in Cohort 2). Nineteen of these 25 participants remained progression-free at the time of the DCO, with a median efficacy follow-up of 49 weeks (range 6–97). In Cohort 2, investigators observed RECIST v1.1 objective responses in 9 of 23 participants (39%), including 8 confirmed responses. Both participants in Cohort 1 continued to exhibit stable disease after two years of follow-up. Updated safety for all participants and updated efficacy for participants with sufficient maturity beyond the 25 summarized here will be presented at the congress. Conclusions: Treatment with [ 212 Pb]VMT-α-NET continues to demonstrate a favorable safety profile across all treated participants (n = 56) and shows signs of sustained efficacy at the 2.5 mCi and 5 mCi dose levels. The therapy has been well-tolerated with no observed dose-limiting toxicities or serious treatment-related adverse outcomes. Based on these encouraging safety and efficacy findings, the study is ongoing, and enrollment into Cohort 3 (6 mCi) remains active. Clinical trial information: NCT05636618 .

Longitudinal changes in patient-reported quality of life (QOL) and hope among early phase cancer clinical trial (EPCT) participants.

11015 Background: Few studies have explored associations of longitudinal changes in patient-reported outcomes (PROs) and clinical outcomes among EPCT participants. We sought to describe changes in hope and QOL over the first two months of EPCT participation and examine associations of these changes with clinical outcomes. Methods: We prospectively enrolled adults participating in EPCTs at Massachusetts General Hospital from 04/2021-01/2023. We assessed QOL (Functional Assessment of Cancer Therapy-General, with subdomains: physical wellbeing [PWB], emotional wellbeing [EWB], social wellbeing [SWB], functional wellbeing [FWB]) and hope (Herth Hope Index) at time of EPCT enrollment, at 1 month (M1), and at 2 months (M2). We used descriptive statistics and regression models to describe changes and explore associations of patient-reported QOL and hope with patient factors (age, diagnosis, performance status) and clinical outcomes (time on trial [TOT], ED visits, and hospitalizations). Results: We enrolled 195 of 251 eligible patients (78% enrollment) and 192 completed surveys (98% response, median age: 63, 57% female, 94% metastatic cancer, ECOG 0 = 47% and ECOG 1 = 58%), 152 (78%) had M1 data, and 114 (59%) had M2 data evaluable. Most common cancer types were gastrointestinal (34%) and breast (20%). Over time, mean QOL scores improved (baseline [B/L] [75], M1 [76], M2 [76]), and mean hope scores were unchanged (B/L [39], M1 [39], M2 [39]). At M1, older age was associated with improved QOL change (B = 3.09, p = .031), EWB change (B = 0.94, p = .036), and increased hope (B = 1.22, p = .013). Female sex correlated with improved FWB (B = 1.15, p = .048) at M2. Head & neck cancer was associated with decreased EWB (B = -2.89, p = .010) at M2. Improved QOL at M2 was associated with longer TOT (HR = 0.97, p = .003). Improved PWB was associated with lower risk of ED visits (HR = 0.94, p = .011) and hospitalizations (HR = 0.95, p = .045) at M1, as well as longer TOT (HR = 0.94, p = .015) and lower risk of hospitalizations (HR = 0.93, p = .022) at M2. Improved EWB was associated with longer TOT at M1 (HR = 0.94, p = .001) and at M2 (HR = 0.89, p = .001). Improved FWB was associated with lower risk of hospitalizations (HR = 0.93, p = .023) at M1, as well as lower risk of hospitalizations (HR = 0.91, p = .043) and longer TOT (HR = 0.92, p = .016) at M2. We found no significant associations of changes in hope scores with clinical outcomes. Conclusions: This prospective study examined longitudinal changes in QOL and hope among EPCT participants. We described changes in QOL and hope scores from time of EPCT enrollment through 1- and 2-month follow-up and identified factors associated with these changes. Improvements in QOL over time predicted higher TOT and reduced healthcare utilization. Future studies should assess and address longitudinal changes in PROs to enhance trial experience and optimize clinical outcomes.

A phase 1 study of HWK-007, a next-generation, protein tyrosine kinase 7 (PTK7)–targeted antibody-drug conjugate (ADC), in patients with advanced solid tumors.

TPS3156 Background: PTK7 is a pseudokinase expressed during embryogenesis and downregulated in normal adult tissue. Aberrant overexpression of PTK7 has been reported in up to 70% of solid tumors and is associated with tumor progression, metastasis, chemoresistance, and poor prognosis. A previous analysis demonstrated particularly high PTK7 expression in non-small cell lung cancer (NSCLC), endometrial carcinoma (EC), and ovarian cancer (OC), across histologic subtypes and disease stages, making PTK7 an attractive therapeutic target with cross-indication applicability (Matulonis et al. AACR-NCI-EORTC 2025, Poster C040). Results from early clinical trials of cofetuzumab pelidotin, a PTK7-targeted, auristatin-based ADC, showed promising clinical activity. HWK-007 is a next-generation, PTK7-targeted ADC comprising an Fc effector-attenuated IgG1 antibody conjugated to the DNA topoisomerase I inhibitor (TOP1i) CPT116. It was designed using novel bioconjugation and advanced linker–payload technologies that enhance intracellular delivery and minimize systemic release of unconjugated TOP1i. This first-in-human, phase 1 trial evaluates HWK-007 in patients with advanced or metastatic solid tumors. Methods: This multicenter, open-label, single-arm, phase 1 dose-escalation (a)/expansion (b) trial is enrolling patients aged ≥18 years with advanced or metastatic NSCLC (non-squamous, epidermal growth factor receptor–wild-type [ EGFR wt]), EC (all histologies), or epithelial OC (all histologies). Patients with NSCLC or EC must have prior treatment with platinum-based chemotherapy and a PD-(L)1 inhibitor, if eligible. Patients with OC must have platinum-resistant disease and prior treatment with standard-of-care therapy. All patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (except in the OC dose-escalation cohorts in which patients with non-target lesions per RECIST and CA125 ≥2 times ULN are permitted), Eastern Cooperative Oncology Group performance status 0 or 1, and no prior treatment with a TOP1i-containing ADC. Patients with clinically active brain metastases or a history of pneumonitis/interstitial lung disease are ineligible. In phase 1a, patients are sequentially assigned to HWK-007 dose levels (DLs; administered intravenously, once every three weeks) using a Bayesian Optimal Interval design (toxicity threshold, 25%), with potential backfill. Backfill cohorts are enriched for patients with EGFR wt NSCLC. Primary endpoints are safety, maximum tolerated dose, and recommended dose for expansion cohorts (phase 1a); and safety and objective response rate (phase 1b). Secondary endpoints include pharmacokinetics and preliminary efficacy outcomes. Recruitment is underway; planned enrollment is up to 226 patients. Clinical trial information: NCT07444814 .

AI-based volumetric vs bidimensional RANO 2.0 progression assessment: Prognostic value for overall survival in glioblastoma.

e14099 Background: Glioblastoma (GBM) presents unique imaging challenges due to irregular morphology. The RANO 2.0 criteria recommends both bidimensional (2D) and volumetric (3D) measurements, yet their comparative prognostic value between two methods needs more evidences. While 2D measurements offer simplicity, they may inadequately capture complex tumor geometry and demonstrate high inter-reader variability. Determining which method provides superior prognostic discrimination is essential for RANO 2.0 implementation in clinical trials. We compared the prognostic value of 2D versus 3D RANO 2.0 assessments in predicting overall survival (OS) and evaluated concordance in progression-free survival (PFS) determination. Methods: Nine newly diagnosed GBM patients from a blinded pooled clinical trial cohort were analyzed. All received standard-of-care treatment. Contrast-enhanced T1-weighted brain MRI was performed at 8-week intervals. Progression was independently determined using RANO 2.0 criteria. Time-dependent Cox regression models, treating progression as time-varying covariates, assessed associations between progression and OS for each method. Kaplan-Meier analysis compared survival outcomes. Results: Among 9 patients 2D RANO detected progression in 6 patients (67%) while 3D RANO identified 5 patients (56%). Median PFS was 54 weeks for both methods, demonstrating high temporal concordance. However, one patient showed 2D-detected progression without meeting 3D criteria, indicating measurement-dependent discordance in 11% of cases. In time-dependent Cox regression, 3D volumetric assessment demonstrated a numerically higher hazard ratio for OS (HR=7.75, 95% CI: 0.73-81.83, p=0.089) compared to 2D assessment (HR=4.53, 95% CI: 0.32-64.72, p=0.27), suggesting stronger prognostic discrimination, though neither reached statistical significance in this pilot cohort due to small sample size. The wider confidence intervals reflect limited sample size but indicate that progression by either method was associated with substantially increased mortality risk. Conclusions: Both 2D and 3D RANO 2.0 assessments provide prognostic value for OS in GBM. Volumetric 3D showed numerically superior discrimination and approached significance despite limited sample size. Findings suggest 3D volumetric measurements may offer enhanced prognostic stratification within RANO 2.0, with implications for clinical trial design and response assessment standardization. Validation in larger cohorts (n= 50 - 60) is planned to definitively establish comparative performance.

Efficacy and safety of donafenib combined with TACE and with/without PD-(L)1 inhibitors for unresectable hepatocellular carcinoma (uHCC): A multicenter retrospective study.

e16212 Background: Donafenib(Dona) have shown superiority over sorafenib in improving OS and has favorable safety and tolerability in Chinese patients with advanced HCC. Transarterial chemoembolization (TACE) can effectively reduce tumor burden by delivering chemotherapy drugs directly to the tumor while blocking its blood supply. This study aims to assess the clinical efficacy of combination therapy (Dona+TACE±PD-(L)1 ) in uHCC and monitor changes in liver function throughout the treatment course. Methods: In this retrospective study, we collected patients diagnosed with uHCC who received a combination therapy of Dona plus TACE with/without PD-(L)1 inhibitors [Dona＋TACE±PD-(L)1 ] as the first-line therapy at The First Affiliated Hospital of Sun Yat-sen University, The First Affiliated Hospital of Guangxi Medical University, The Third Affiliated Hospital of Sun Yat-sen University, The First People's Hospital of Foshan and The Affiliated Cancer Hospital and Institute of Guangzhou Medical University from January 2022 to July 2025. The primary endpoint was progression-free survival (PFS) according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST), secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Results: A total of 142 patients were enrolled (53 in Dona＋TACE group, 89 in Dona＋TACE ＋PD-(L)1 group ). Among all patients, median age was 59 years, 129 patients (90.8%) were male, 79(56.0%) were at BCLC stage C. Most of the disease etiology was HBV (82.4%), 103 (72.5%) had cirrhosis. Most patients had multiple lesions (75.4%), hepatic venous invasion was observed in 63 (44.4%) of the patients, median maximum tumor diameter was 7.3cm (IQR, 4.9-10.3). Most patients had good liver function reserve (Child-pugh A, 78.2%; ALBI grade1, 25.7%; ALBI grade2, 67.1%). The median number of TACE sessions per patients was 2 (IQR, 1-4). Up to the date of January 12,2026, the median follow-up was 22.8 months. The median PFS was 11.6 months (95%CI: 8.8-14.4), and the PFS rates at 6months and 12 months were 72.0% and 48.5%, respectively, the OS rates at 1 year and 2 years were 80.3% and 63.8%, respectively. Based on the mRECIST criteria, the best ORR and DCR were 69.7% (n = 99) and 95.1% (n = 135), respectively. For Dona＋TACE group and Dona＋TACE ＋PD-(L)1 group, the ORR was 67.9% and 71.0%, respectively. Among the 113 evaluable patients, 89 patients (78.8%) maintained or improved ALBI grading at the end of treatment. 41.5% of patients experienced any grade treatment-emergent adverse events (TEAEs), while only 12.7% of patients experience grade 3 or 4 TEAEs, and no treatment-related deaths occurred. Conclusions: Donafenib plus TACE and with/without PD-(L)1 inhibitors showed encouraging antitumor activity and manageable safety, which maybe a potential regimen option for uHCC.

Prevalence of dental caries in the primary, mixed and permanent dentitions in Nigeria: A systematic review and meta-analysis

Background The national prevalence of dental caries in Nigeria is currently unknown. The objective of this systematic review and meta-analysis was to determine the prevalence of dental caries in the primary, mixed and permanent dentition among residents in urban, rural and semi-urban Nigeria. Methods A systematic search was conducted in PubMed, Web of Science, Scopus, CINAHL and Embase databases and Google Scholar for studies published between January 2001 and December 2023 reporting the prevalence of dental caries in Nigeria. The review was registered with PROSPERO (CRD42022362019) and conducted in accordance with the PRISMA guidelines. Data extracted included study design, sample size, age of participants, and study location. Study quality and risk of bias were assessed. A random-effects meta-analysis was performed to estimate pooled prevalence. Results A total of 1,010 records were identified, of which 52 studies were included in the systematic review and 35 were eligible for meta-analysis. Most studies were conducted in Southwestern Nigeria. The overall pooled prevalence of dental caries in Nigeria was 17% (95% CI: 14%–21%; I² = 97%). The pooled prevalence was 16% (95% CI: 10%–24%; I² = 98%) in primary dentition, 16% (95% CI: 11%–23%; I² = 97%) in mixed dentition, and 20% (95% CI: 16%–26%; I² = 96%) in permanent dentition. By setting, the pooled prevalence was 22% (95% CI: 7%–52%; I² = 98%) in rural areas, 17% (95% CI: 14%–22%; I² = 97%) in semi-urban areas, and 14% (95% CI: 6%–29%; I² = 98%) in urban areas. Substantial heterogeneity was observed across studies. Conclusion Dental caries remains a significant public health concern in Nigeria, affecting approximately one in five individuals. Although variations were observed across dentition types and geographic settings, substantial heterogeneity indicates diverse epidemiological contexts across the country. Strengthened preventive strategies and improved access to oral healthcare services are needed to address the burden of dental caries nationwide.

Wavelength- and intensity-tunable self-powered bipolar photodetectors based on a-Ga2O3 heterostructures for encrypted communication

Bipolar photodetectors are promising for optical logic and communication but often suffer from structural complexity and high power consumption. Here, we report a self-powered, vertical photodetector based on an ITO/Au NPs/a-Ga2O3/Pt heterojunction. By leveraging Au nanoparticles to engineer interfacial oxygen vacancies and the synergistic modulation of the Schottky barrier by the light field, the device achieves a distinct bidirectional photoresponse at zero bias. Specifically, it exhibits wavelength-dependent polarity switching, generating positive photocurrent at 254 nm and negative at 310 nm. Notably, under 295 nm illumination, the device displays an anomalous intensity-dependent polarity reversal, transitioning from negative to positive as light intensity increases. We demonstrate the potential of these tunable features in optical logic gates and encrypted communication systems, offering a new pathway for multifunctional self-powered optoelectronics.

Novel synthesis of mordenite from magadiite transformation with assistance of ·OH in template-free system

Actuation of Cell Layers in Three Dimensions

ABSTRACT The alignment of fibers and cells in living tissues affect their mechanical properties and functionality. In this context, one can draw an analogy between tissues and nematic liquid crystal elastomers. We explore this analogy by growing fibroblasts on 2D‐patterned substrates and observing the contraction of cell sheets upon detachment from the substrates. When fibroblast sheets detach, they undergo an anisotropic contraction, with maximum contraction along the nematic director, like nematic elastomers do during phase transition. We quantify this anisotropy using substrates patterned with stripes to induce alignment, finding that cell sheets resemble nematic elastomers with negative 2D Poisson ratio. The contraction of the peeling sheet is robust to drugs that modulate cytoskeletal remodeling. We then apply design principles used for programming curvature in nematic elastomers to actuate 3D structures in the detached fibroblast layers, demonstrating an application of these principles and we support the results with simulations. This proof of concept shows the ability to control the 3D shape through 2D patterning in cell layers, leading to promising avenues to program tissues.

Comparative response of root-associated soil bacterial communities to phytophthora blight in healthy versus diseased Panax notoginseng plants

Extracellular ATP drives tryptophan metabolism and aryl hydrocarbon receptor activation to promote cellular senescence

A multicenter, randomized controlled phase III trial of TPF induction chemotherapy versus PF adjuvant chemotherapy combined with concurrent chemoradiotherapy in locally advanced nasopharyngeal carcinoma: Long-term follow-up analysis.

6100 Background: To investigate whether TPF induction chemotherapy combined with concurrent chemoradiotherapy (CCRT) can provide greater survival benefits compared to CCRT followed by PF adjuvant chemotherapy. Methods: Patients with newly diagnosed locally advanced (Stage III–IVA) nasopharyngeal carcinoma (NPC) treated at the Affiliated Tumor Hospital of Guizhou Medical University, the Second Affiliated Hospital of Guizhou Medical University, the Second Affiliated Hospital of Zunyi Medical University, and Guiyang Hospital of Guizhou Aviation from May 2018 to July 2021 were enrolled. Each group included 133 patients. The experimental group received 3 cycles of TPF induction chemotherapy (docetaxel 75mg/m²,intravenous infusion, Day 1; cisplatin 75mg/m²,continuous intravenous infusion over 5 days,10:00–22:00 daily; fluorouracil 750mg/m²/day, continuous intravenous infusion over 5 days, 22:00–10:00 daily) followed by 2–3 cycles of concurrent chemotherapy (cisplatin 100mg/m², continuous intravenous infusion over 2 days, 10:00–22:00 daily). The control group received PF adjuvant chemotherapy (cisplatin 80mg/m², continuous intravenous infusion over 5 days,10:00–22:00 daily; fluorouracil 800mg/m²/day, continuous intravenous infusion over 5 days, 22:00–10:00 daily) combined with 2–3 cycles of concurrent chemotherapy (same as induction chemotherapy).Both groups underwent intensity-modulated radiotherapy (IMRT),with total doses of 69.96 Gy for T1–T2 primary lesions, 72.6 Gy for T3–T4 lesions, and 69.96 Gy for positive lymph nodes. Data were analyzed using SPSS 26.0.Differences in 5-year PFS, OS, LRFS, DMFS, and adverse events were compared between the two groups. Results: No significant differences were observed between the two groups in age, sex, Karnofsky Performance Status (KPS) score, T stage, N stage, or overall stage ( P > 0.05).At a median follow-up of 58 months, the 5-year PFS in both the intention-to-treat and per-protocol populations was similar between the induction chemotherapy (IC) and adjuvant chemotherapy (AC) groups (66.6% vs 66.0%, P = 0.589; 75.3% vs 69.9%, P =0.471). The 5-year OS, LRFS, and DMFS rates were 73.0% vs 71.3% ( P =0.582), 87.4% vs 90.8% ( P =0.508), and 76.9% vs 72.6% ( P =0.267), respectively, with no significant differences. Conclusions: Both groups had similar 5-year PFS, OS, LRFS, DMFS, and long-term toxicity profiles. Clinical trial information: NCT03574324 . 5-year observation indicators for two groups. Observation indicators IC+CCRT CCRT+AC P value Risk ratio(95% CI) PFS ITT Population 66.6% 66.0% 0.589 0.89（0.58-1.36） PP Population 75.3% 69.9% 0.471 0.85（0.55-1.33） OS 73.0% 71.3% 0.582 0.88（0.55-1.39） LRFS 87.4% 90.8% 0.508 1.30（0.60-2.80） DMFS 76.9% 72.6% 0.267 0.75（0.45-1.25） OS, LRFS, and DMFS were all calculated in the ITT population.

Gabapentin plus intranasal ketamine for the prevention and treatment of pain in patients undergoing radiotherapy for head and neck cancer: Phase II trial results.

12135 Background: Prophylactic gabapentin decreases pain, opioid use, and weight loss in head and neck (HNC) patients treated with chemoradiotherapy. Nonetheless, significant symptom burden remains. Ketamine is an NMDA receptor antagonist which has neuromodulator and anti-inflammatory properties. We undertook a phase I/II study to explore safety, feasibility, and obtain preliminary efficacy data pertaining to the combination of ketamine and gabapentin in HNC patients undergoing radiation +/- chemotherapy. Results of the phase I study were previously reported. Herein we report preliminary results of the phase II portion of the study. Primary outcomes were toxicity and feasibility; secondary outcomes were symptom burden. Methods: Eligibility: locally advanced HNC patients planned for primary or adjuvant radiotherapy +/- chemotherapy. Treatment: Day 1: gabapentin 100 mg PO TID; Day 8: increase gabapentin to 300 mg PO TID; Day 15: continue gabapentin and start intranasal ketamine 30 mg TID. Dose modifications were allowed for both agents. Toxicity: assessed using CTCAE 5.0. Feasibility: data capture by pill counts and patient medication logs. Efficacy: patient reported outcomes measures completed at baseline, weekly during radiation and 1-, 2-, and 3-months post-radiation. Results: Patient characteristics: median age 60 yrs, 85% males, 67% p16-positive, 21 post-operative. Toxicity: Of 45 patients who completed treatment, 7 patients (16%) experienced a grade 2+ toxicity (5 were probably related to ketamine). Four patients required ketamine dose de-escalation due to dizziness. Six patients (13%) eventually discontinued ketamine due to toxicity. Feasibility: 41 (91%) patients missed <5% of gabapentin doses; 35 (78%) patients missed <5% of ketamine doses. Preliminary Efficacy: Eight patients (18%) required PEG placement. median score on the pain subscale of the Vanderbilt Head and Neck Symptom Survey 2.0 was highest at the end of treatment (4.3/10) and decreased rapidly (2.4/10 at 1 month and 1.7/10 at 2 months post-treatment). During treatment, 8 patients (18%) required no opioids, and 24 patients (55%) required immediate-release (IR) opioids only. The median of the maximum morphine milligram equivalent (MME) per day for IR opioids alone was 90 MME/day(range 10 – 180 MME/day). The median duration of IR prescription alone was 30 days (range 10 – 347 days). Twelve patients (27%) required addition of extended-release (ER) opioids with a median duration 35 days (range 28 - 220 days). Only 3 patients (7%) required ER opioids for >90 days. Conclusions: The combination of gabapentin and ketamine was safe and feasible. Preliminary data indicates the majority of patients experienced low to moderate levels of pain with minimal use of opioids. Larger, randomized studies are warranted to confirm the benefit of the combination of gabapentin and ketamine. Clinical trial information: NCT05156060 .

Difference-in-differences analysis of age-specific survival gains in acute myeloid leukemia following venetoclax approval.

e23058 Background: Venetoclax in combination with a hypomethylating agent or low-dose cytarabine received accelerated approval from the FDA in 2018 for older or unfit patients with acute myeloid leukemia (AML). Prior real-world studies have sought to evaluate the impact of venetoclax approval, but they have used non-experimental statistical approaches that cannot disentangle venetoclax-specific effects from broader time-related improvements in AML outcomes. To address this limitation, we analyzed age-specific changes in AML survival using a quasi-experimental difference-in-differences (DiD) approach. Methods: We included all patients diagnosed with AML at age 20 or older between 2013 and 2022 in the Surveillance, Epidemiology, and End Results (SEER) 21 registry. Age was categorized into four groups (20-49, 50-64, 65-74, and ≥75), consistent with age ranges represented in venetoclax clinical trials, plus a younger comparison group. Parallel trends between age groups were assessed in the pre-venetoclax period (2013 – 2017), and DiD analyses compared outcomes before and after venetoclax approval, with 2018 excluded as a transition year. Primary outcomes included 1-year overall survival (OS) for 2013-2021 and use of cancer-directed agents for 2013-2022. Models were adjusted for race and sex. Wald tests were used for statistical inference. Results: Of the 59,676 patients with AML included, 15% were aged 20-49 years, 23% were 50-64, 27% were 65-74, and 35% were ≥75. Most patients were non-Hispanic White (68%) and male (55%), and 72% received cancer-directed agents. Pre-venetoclax trends in 1-year OS and cancer-directed agent receipt were parallel across age groups (Table). Following venetoclax approval, improvements in 1-year OS increased progressively with age: compared with 20–49-year-old patients, relative gains were 1.1% for ages 50–64 (p=0.5), 3.3% for ages 65–74 (p=0.02), and 4.2% for ages ≥75 (p<0.001). Similarly, post-approval increases in cancer-directed agent receipt were progressively larger with increasing age: compared with 20–49-year-old patients, relative gains were 1.9% for ages 50-64 (p=0.07), 4.7% for ages 65-74 (p<0.001), and 9.8% for ages ≥75 (p<0.001). Conclusions: Using a quasi-experimental DiD approach, we demonstrate that venetoclax approval was associated with greater improvements in 1-year OS and receipt of cancer-directed agents for older adults with AML. These findings suggest that the 2018 accelerated approval of venetoclax led to meaningful improvements in outcomes for patients with AML historically ineligible for standard induction chemotherapy. Age OS Slope (pre) (%/yr) p-value Treatment Slope (pre) (%/yr) p-value 1-yr OS (pre) 1-yr OS (post) %Tx (pre) %Tx (post) 20-49 1.06 - 0.43 - 75.2 75.4 90.7 90.1 50-64 0.59 0.37 0.22 0.68 54.7 55.8 85.1 86.2 65-74 -0.18 0.09 0.35 0.85 36.8 40.1 75.9 80.0 >75 0.74 0.54 1.41 0.07 18.3 22.6 49.8 59.0

Outcomes of osimertinib rechallenge after osimertinib-induced interstitial lung disease in metastatic EGFR-mutated NSCLC: Systematic review and meta-analysis.

e20732 Background: Osimertinib is standard therapy for metastatic EGFR-mutated (mEGFR+) NSCLC but rarely causes pneumonitis/interstitial lung disease (ILD). After recovery, rechallenge may allow continued benefit, but the safety of rechallenge varies between studies and remains unknown. Methods: We conducted a systematic review & meta-analysis (PROSPERO: CRD420261290112). MEDLINE and Embase were searched from inception to July 17, 2025. Eligible studies were cohorts or case series (≥2 patients) of adults with mEGFR+ NSCLC who developed osimertinib-associated ILD and were subsequently rechallenged with osimertinib after improvement or resolution. Comparators, when reported, included switching to other EGFR-TKIs or other treatments (i.e. chemotherapy). Primary outcomes were recurrent ILD, grade ≥3 ILD, or fatal (grade 5) ILD recurrence. Random-effects meta-analyses of proportions and risk ratios were performed in R. When individual patient data (IPD) was available, time to recurrent ILD was summarized descriptively. We also explored the association between initial ILD grade and severe recurrence (grade ≥3) using Fisher’s exact test. Results: Seven studies were included: 98 patients rechallenged with osimertinib and 96 switched to another EGFR-TKI. Median ages ranged from 64-75 years, and 60.4% were female. Of studies that reported initial ILD severity, 50% (32) were Grade 1, 32.8% (21) were Grade 2, 14.1% (9) were Grade 3, and 3.1% (2) were Grade 4. Pooled recurrent ILD after osimertinib rechallenge was 32.2% (95%CI, 20.2–47.2) versus 15.6% (95%CI, 9.6–24.3) after EGFR-TKI switch (RR 2.01, 95%CI 1.10–3.68, I 2 = 5.8%, p = 0.02). Three fatal ILD recurrences occurred after osimertinib rechallenge, all from a study with 50% of patients with initial ILD grade ≥3. One fatality was reported after alternative EGFR-TKI in the same study. Of 18 patients with a recorded time to recurrent ILD, the median time to recurrence was 2.05 months (IQR 1.00-4.25). In exploratory IPD, severe initial ILD predicted severe recurrence (initial grade 3–4: 4/4 with recurrent grade ≥3 vs initial grade 1–2: 1/11 with recurrent grade ≥3; Fisher p≈0.004). Conclusions: Osimertinib rechallenge after osimertinib-induced ILD carries a substantial recurrence risk and approximately double the recurrence versus switching to non osimertinib EGFR-TKI, with events occurring early. These data support that rechallenge may be reasonable after low-grade ILD in carefully selected patients, but should likely be avoided after high-grade initial ILD, given the risk of severe or fatal recurrence.

Correlation between <i>CARINH</i> expression and clinical outcomes in metastatic clear-cell renal cell carcinoma (mccRCC).

4553 Background: CARINH is an interferon (IFN)-responsive long non-coding RNA that promotes IRF1 expression and downstream IFN signaling. Higher CARINH expression improves outcomes in esophageal cancer through suppressed tumor growth (Huang et al, 2019). Despite the immunogenic nature of RCC, the role of CARINH in its immunogenicity remains unexplored. Here, we examine the role of CARINH in predicting progression in mccRCC patients (pts) treated with systemic therapy. Methods: We included pts with RNA-seq data from 2 first-line clinical trials in mccRCC: Javelin Renal-101 (JR; n = 741) and CheckMate9ER (CM9; n = 403). Transcripts per million (TPM) were log2-transformed and scaled per 1 SD change. IMmotion150 T eff and Myeloid signatures, and tumor inflammatory score (TIS) were computed as means of their log2-transformed genes’ TPMs then scaled. Multivariable (MV) Cox models assessed progression-free survival (PFS) per increase in CARINH expression and compared PFS for each immune signature with and without CARINH expression, using likelihood ratio test (LRT). Log-rank test compared PFS between high and low CARINH expression groups with median split. Spearman correlation associated CARINH expression and immune signatures. MV logistic regression estimated progression odds ratio between pts who progressed (RECIST 1.1: PD), and those who didn’t (CR, PR, SD and NCR/NPD). MV analyses adjusted (adj) for age, sex, treatment arm, IMDC risk and sarcomatoid features. Results: In MV Cox analysis, higher CARINH was associated with improved PFS in both trials (JR: HR adj = 0.87 - 95% CI: 0.79-0.96, p = 4.5×10 -3 ; CM9: HR adj = 0.82 - 95% CI: 0.73-0.93, p = 1.3×10⁻³), regardless of treatment arm (LRT p &gt; 0.05). Log-rank test, comparing high and low expression groups, revealed longer PFS with high expression in every cohort and their arms (p &lt; 0.05), except for sunitinib in CM9 (p = 0.18). Higher CARINH expression correlated positively with T eff and TIS signatures (ρ = 0.51-0.54) and negatively with Myeloid signature (ρ = −0.14 to −0.10) in both trials (p &lt; 0.05). CARINH expression improved PFS prediction over immune signatures in both trials (Table). Higher expression was associated with lower progression odds (JR: OR adj = 0.74 - 95% CI: 0.60–0.91, p = 3.7×10⁻³; CM9: OR adj = 0.68 - 95% CI: 0.47–0.98, p = 0.04), independent of arm (LRT p &gt; 0.05). Conclusions: In mccRCC, higher CARINH expression associates with lower progression odds and improved PFS beyond that predicted by immune signatures. Translational efforts to characterize its role in mccRCC pathophysiology and clinical outcomes are ongoing. MV Cox for PFS prediction by immune signature after adding CARINH expression. Trial Immune Signature HR adj (with CARINH) 95% CI LRT FDR-adj p-value JR TIS 0.86 0.76-0.97 0.02 JR T eff 0.88 0.79-0.99 0.04 JR Myeloid 0.87 0.80-0.96 0.02 CM9 TIS 0.84 0.72-0.97 0.02 CM9 T eff 0.81 0.70-0.94 7.2×10⁻³ CM9 Myeloid 0.82 0.73-0.93 4.6×10⁻³

Organ preservation strategy using dostarlimab for dMMR/MSI-H resectable solid tumors with whole-genome–based MRD monitoring (D-CURE: EPOC2401).

TPS2697 Background: Mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) solid tumors accumulate numerous genomic alterations that generate neoantigens, which are presented on MHC molecules and activate potent Th1 and cytotoxic T-cell responses. This heightened immunogenicity simultaneously induces adaptive immune resistance through PD-1/PD-L1 upregulation, providing a strong biological rationale for the effectiveness of immune-checkpoint inhibitors in dMMR/MSI-H tumors. Neoadjuvant immune-checkpoint inhibition is particularly effective in dMMR/MSI-H tumors because it leverages the intact tumor and lymphatic microenvironment to prime robust systemic antitumor immunity before surgical removal. Standard surgery for solid tumors varies widely depending on the cancer type, but it carries risks of functional impairment and postoperative morbidity. Therefore, nonoperative management (NOM) has emerged as a clinically meaningful strategy to preserve organ function and improve patients’ quality of life. Methods: D-CURE is a multicenter phase II trial evaluating whether dostarlimab, an anti–PD-1 IgG4 humanized monoclonal antibody, can safely achieve clinical complete response (cCR) and enable NOM with organ preservation in patients with dMMR/MSI-H resectable solid tumors (excluding colorectal cancer). Patients will receive 9 cycles of dostarlimab (500 mg/body every 3 weeks). Observation with NOM will be offered to patients who achieve cCR or near-cCR. Patients undergoing NOM will be followed for up to 2 years from the date of enrollment. The primary endpoint is the 12-month cCR rate after dostarlimab. Key eligibility criteria are as follows: untreated malignancy (excluding colorectal cancer); dMMR/MSI-H confirmed in tissue or blood; age ≥18 years; ECOG PS 0–1; and clinical stage eligible for surgical resection, definitive radiotherapy, or definitive chemoradiotherapy according to the TNM 8th Edition. The target sample size of 80 was determined based on 90% power, a one-sided alpha of 5%, a threshold 12-month cCR rate of 38%, and an expected 12-month cCR rate of 56%. We also integrate personalized precise molecular residual disease (MRD) monitoring incorporating up to 1,000 tumor-specific alterations identified through whole-genome sequencing of tumor tissue, with serial ctDNA-based MRD assessment and parallel enrollment in the MONSTAR-SCREEN-3 study (UMIN000053975). Through this linkage, patients will also have access to the multi-omics platform, enabling spatial transcriptomics, bulk WES/WTS, plasma proteomics, and microbiome analyses to elucidate tumor-immune dynamics and comprehensively characterize treatment response and resistance. Enrollment of the D-CURE trial started in September 2025 and is ongoing at 12 facilities in Japan. Clinical trial information: jRCT2031250364.

Cross-modality AI modeling of histopathology images to stratify outcomes among patients treated with hormonal or chemo-hormonal therapy in ER+/HER2− breast cancer.

1028 Background: Oncotype DX (ODX) is widely used to guide adjuvant treatment decisions in early-stage ER+/HER2− breast cancer. However, ODX provides limited stratification of residual metastatic risk within patients receiving hormonal therapy (HT) alone or hormonal therapy following chemotherapy (HT+CT). We developed a cross-modality AI approach that derives risk scores directly from routine H&amp;E-stained whole-slide images (WSIs) to stratify metastatic outcomes among patients receiving standard adjuvant therapies. Methods: Using a cross-modality transfer learning framework, we first developed genomic biomarkers by mapping RNA-seq data to distant metastatic outcomes by integrating thousands of genes and signaling pathway activities in the publicly available ScanB dataset. Deep learning models were then trained to infer these biomarkers directly from WSI of breast tumors using the TCGA dataset. External validation was performed in an independent cohort of 287 early-stage ER+/HER2−, node-negative patients from MD Anderson Cancer Center. Among these, 147 patients with ODX&lt;25 received HT alone, while 140 patients with ODX&gt;25 were included, 121 of whom received HT+CT. Kaplan–Meier survival analysis, log-rank tests, and Cox proportional hazards models were used to evaluate outcome stratification within each treatment group. Results: Among patients treated with HT alone, AI score stratified metastatic outcomes (HR=2.75; p &lt;0.01), identifying patients who developed distant recurrence despite low ODX scores. Among patients treated with HT+CT, AI score also stratified outcomes (HR=3.94; p &lt;0.03), identifying patients who experienced metastasis despite combination therapy. Across treatment groups, AI score provided prognostic information beyond ODX and clinicopathologic variables. In multivariable analyses adjusting for ODX and clinical covariates, AI score remained independently associated with metastatic risk and demonstrated consistent stratification across clinically relevant subgroups. Validation of these findings in an expanded cohort is ongoing. Conclusions: This AI-based approach further stratifies outcomes among patients receiving HT or HT+CT as guided by ODX, directly from routine histopathology images in early-stage ER+/HER2− breast cancer. Thus, integration of AI-derived outcome stratification with ODX scores may improve individualized treatment decision-making and support consideration of alternative therapies.